The endogenous formation of nitric oxide (NO) plays a key role in many bio-regulatory systems including immune stimulation, platelet inhibition, neurotransmission, and smooth muscle relaxation (Wang, P. G., Xian, M., Tang, X., Wu, X., Wen, Z., Cai, T., Janczuk, A. J. Chem. Rev. 2002, 102, 1091-1134). Due to the instability and inconvenience of handling aqueous solutions of NO, there is increasing interest in compounds capable of generating NO in situ, i.e., NO donors.
All nitrogen-oxygen bonded compounds have the potential to decompose, be oxidized, or be reduced to produce reactive nitrogen species. Accordingly, a diverse range of NO donors has been developed including organic nitrates and nitrites, metal-NO complexes, N-nitrosamines, thionitrites, furoxans and benzofuroxans, oximes and N-hydroxyguanidines. However, the NO donors developed to date are poorly taken up by cells and are not targeted to particular compartments of the cell. Therefore, the presently known NO donors mainly produce NO in the circulation and thus expose a range of NO receptors to NO.
S-Nitrosylation (also referred to as S-nitrosation) is the post-translational addition of a nitrosyl group to a protein. In addition to releasing free NO, NO donors can also transfer a nitrosonium group to a protein thiol to form an S-nitrosylated product. The modulation of S-nitrosylation may be involved in regulating a number of pathways important in cell metabolism (Nature Reviews: Molecular Cell Biology, 2005, 6:2, pp 150-166).
Recently, it has been shown that cytochrome c oxidase (complex IV of the mitochondrial respiratory chain) is reversibly inhibited by NO (Brown, G. C. and Cooper, C. E. FEBS Lett. 1994, 356, 295-298; Cleeter, M. J. W., Cooper, J. M., Darley-Usmer, V. M., Moncada, S. and Schapira, A. H. V. FEBS Lett. 1994, 345, 50-54; Schweizer, M. and Richter, C. Biochem. Biophys. Res. Commum. 1994, 204, 169-175).
This may be a physiologically relevant mechanism to limit oxygen consumption, mitochondrial ROS (reactive oxygen species) production, apoptosis and mitochondrial biogenesis and morphology.
Transfer of the nitrosonium group to protein thiols may also be involved in regulating mitochondrial function, for example at complex I (Dahm, C. C., Moore, K., Murphy, M. P., J. Biol. Chem. 2006, 281, pp 10056-10065). S-Nitrosylation of particular mitochondrial thiol proteins such as complex I may play a protective role in conditions such as ischaemia-reperfusion injury (Journal of Molecular and Cellular Cardiology, 2007, 42:4, pp 812-825).
In order to investigate this function of NO, it would be useful to have a NO donor compound that selectively released NO in the mitochondria. In addition, a number of medical conditions are influenced by the selective, reversible inhibition of mitochondria. Therefore a mitochondrially targeted NO donor would have potential as a therapeutic agent.
It is therefore an object of the invention to provide a targeted NO donor compound, or at least to provide the public with a useful choice.